We are studying the mechanisms responsible for incomplete penetrance of the renal agenesis phenotype of the mouse mutant limb deformity (ld). The ld gene encodes four alternatively-spliced isoforms (I-IV). Several alleles of ld mutations have arisen on different genetic backgrounds, three of which are ldBri, ldIn2, and ld J. The ldBri and ldIn2 mutants have a 20-30% penetrance of renal abnormalities, whereas the ldJ mutants have a 98% penetrance. Isoform IV null mice (ldG/ldG) generated by gene targeting have a 6% incidence of renal agenesis, yet have perfectly normal limbs, indicating the limb and kidney phenotypes are separable in the ldG/ldG mice. In various combinations of compound ld heterozygotes. preliminary results indicate that the renal abnormalities correlate with the ld allele, thus suggesting that it is the mutation itself, not the genetic background, that governs the penetrance of renal agenesis at this locus.